tbuckley/cabot-search huggingface dataset:
CAR-T therapy access with Louisiana Medicaid: A single institution retrospective analysis.
Authors: Suma Sri Chennapragada, Millicent Amankwah, Jaren Lobato Lerner, Runhua Shi, Poornima Ramadas
Journal: Journal of Clinical Oncology (2023)

e18580 Background: Chimeric antigen receptor (CAR)-T therapy has revolutionized the treatment of hematologic malignancies over the past few years. Axicabtagene-ciloleucel was initially approved by the food and drug administration in October 2017 for relapsed/refractory diffuse large B cell lymphoma (DLBCL) after 2 or more lines of systemic therapy. In April 2022, it was approved as second-line therapy for DLBCL that is refractory to first-line or relapses within 12 months of chemoimmunotherapy. Studies have reported complete responses in 50-60% and prolongation of overall survival by 12-18 months. However, CAR-T remains an expensive therapy that can cost up to 1 million USD. Accessibility to CAR-T is governed by various socioeconomic factors including insurance status. The state of Louisiana currently does not have any institution which offers CAR-T therapy. Our Medicaid population is further disadvantaged by the fact that their insurance does not cover out-of-state services. Hence, we conducted this institutional study to evaluate the accessibility to CAR-T and the factors associated with it. Methods: Our retrospective study included adult patients with a diagnosis of DLBCL treated at LSU Shreveport between January 2018 to December 2022. We excluded all other types of B-cell lymphomas, prisoners, and pregnant women. Our primary objective was to evaluate whether the lack of access to CAR-T due to insurance status affected mortality. Our secondary objective was to examine the various demographic factors associated. Analysis was conducted using SAS. Descriptive statistics, Chi-square tests were used to report the results. Results: Our study included a total of 84 patients with a mean age of 59 years. 58% were Caucasian and 38% were African American. 65% were male. 33% had Medicaid coverage and 31% had Medicare. 60% had advanced-stage DLBCL, and 40% had early-stage (Stages I and II). 6% had either double-hit or triple-hit lymphomas. 17% of patients were considered eligible for CAR-T at relapse as per clinician discretion. 33% of patients who were eligible could not get a referral for CAR-T due to factors like insurance status and costs associated with out-of-state living. This led to an increased mortality of 60% in that cohort vs 0% in those who got referrals (p-value of 0.02). Medicaid was the predominant insurance (67%) among those who were unable to get referrals for CAR-T, thus strengthening our hypothesis. Conclusions: Through our study, we aim to bring to light the disparity faced by Louisiana Medicaid patients wherein they don’t have access to a potentially curative therapy for DLBCL. While we do recognize the expenses associated with CAR-T, we wish to highlight that not all states have direct access to this therapy. Seeing how our patients must already uproot their lives temporarily to get CAR-T, their decision could be made easier if insurance can cover the cost at least on a case-to-case basis.
Phase I clinical trial using a unique immunotherapeutic combination of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of patients with advanced esophageal cancer.
Authors: Size Chen, Yiguang Lin
Journal: Journal of Clinical Oncology (2023)

e16061 Background: Combining CAR-T with programmed cell death-1 (PD-1) inhibition may be a more efficacious approach for treatment of solid tumors. This clinical study was designed to assess the safety and tolerability of PD-1 knockout MUC1-Targeted CAR-T engineered Cells to treat advanced esophageal cancer. Methods: Patients with advanced esophageal cancer were recruited according to the criteria in NCT03706326. PD-1 gene knockout (KO) MUC1-targeted CAR-T cells were prepared by constructing MUC1-specific CARs using the SM3 scFv in patient-derived T-cells, and PD-1 gene KO was achieved in these CAR positive T cells using the CRISPR-Cas9 system. Efficiency and validation were confirmed by sequencing and flow cytometry. MUC1-CAR+/PD-1- KO engineered T cells at a starting dose of 5x10 7 were infused over 60 min. The dose was escalated to 5x10 9 cells. Following treatment, the safety and tolerability of dose of the therapeutic cells were assessed using CTCAE v4.0. Patients’ general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored at regular intervals. Circulating CART cells were checked regularly. Tumor size were examined by MRI/CT scans. Efficacy was also assessed. Results: A total of 9 patients (aged 48 to 80) diagnosed with esophageal cancer/esophageal squamous cell carcinoma (IIIb to IV), were included in this study. All participants received at least one cycle of CART cell treatment. Among the 9 treated patients, 4 received 1 cycle, other 5 received 2, 3, 4, 7 and 10 cycles, respectively. The most common adverse events (AE) were acute fever (8 patients, 38.0-40.5 C◦), chills (5 patients, occurred in the subsequent cycle of infusion), skin rash (4 patient). No grade 3-5 AEs were found, and no cytokine release syndrome (CRS) was observed. Of the 9 assessed patients, 6 had stable disease (SD) while 3 had progressive disease. All patients had significant symptom improvements after infusion. Circulating CART cells gradually declined after infusion; the number dropped down to approximately 25% in 4 months after one cycle treatment indicating the necessity of receiving more cycles. Patients who received multiple cycles of infusion showed long-term and steady SD status. Two patients who received a multiple cycle of CAR-T cells had an overall survival (OS) of 24 months. Conclusions: Our data suggests that the treatment of patients with advanced esophageal cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients. No CRS and other serious EAs were observed throughout the study. The efficacy of this unique combined therapy is currently being assessed. Our limited data indicate that the OS of the patients extended significantly in the treated patients. Two out of 6 patients with an OS of greater than 24 months, an outstanding clinical outcome. Clinical trial information: NCT03706326 .
Co-mutation-based subtyping of Chinese patients with gastric cancer.
Authors: He Huang, Zhimin Wang, Hao Chen, Yafei Cheng, Hui Liu, Shaoxiong Bai, Yaoliang Huo, Yanwu Zeng, Leilei Lu
Journal: Journal of Clinical Oncology (2023)

e16070 Background: The incidence of gastric cancer is decreasing globally, in contrast, that of Chinese patients has been increased from 35.9% to 48.3%. In-depth investigation of the characteristic of Chinese gastric cancer patients could help to understand the disease mechanism and improve the treatment of gastric cancer. Methods: Tumor tissues were obtained from 96 Chinese gastric cancer patients and tested by high-coverage ( &gt; 1000x) panel sequencing containing 624 cancer-related genes. Genomic mutations including substitutions, insertions, deletions, rearrangements, fusions, and copy number variations were called. Genes were clustered based on their co-mutation relationship in all samples. Patients with gene mutations in each cluster were classified into corresponding groups. The properties of each patient group were characterized, including genomic features, age, gender, stage, LAUREN type, and grade. Results: The most mutated genes were TP53, ERBB4, LRP1B, and CDH1 in our cohort. A higher proportion of female patients had TP53 mutations compared to male patients. Mutations in ALK, KMT2C, and LRP2 were positively associated with microsatellite-instable, and that in ERBB4 and PIK3CA were positively associated with high tumor mutation burden (TMB). Four gene clusters (1, 2, 3, and 4) were identified based on the co-mutation relationship between genes. Cluster 1 included FAT4, APC, OBSCN, and GATA3; Cluster 2 included FGF3, CCND1, FGF19, and GATA4; Cluster 3 included BLK, FAM135B, and DLC1; and Cluster 4 included ATRX, KMT2D, STAG2, and EGFR. Patients were classified into the four patient groups (I, II, III, and IV) accordingly when mutations in the corresponding gene cluster were found. Further association analysis indicated that: Group I was associated with adenocarcinoma subtype; Group II was negatively associated with LAUREN type 2; Group III was associated with high TMB; Cluster IV was associated with microsatellite-instable. Conclusions: This study utilized gene co-mutations to classify gastric cancer patients into subgroups with unique clinical characteristics. Further study on the etiology, treatment, and prognosis of these groups of patients is needed.
NeoTACE: A multicenter, randomized study evaluating the efficacy and safety of neoadjuvant HAIC for TACE plus donafenib in BCLC B stage hepatocellular carcinoma outside of up-to-seven.
Authors: Xiaodong Wang
Journal: Journal of Clinical Oncology (2023)

TPS4186 Background: Transarterial chemoembolization (TACE) is standard treatment for hepatocellular carcinoma (HCC) patients in BCLC B stage, while a number of studies demonstrated compromised effect of TACE for patients with large HCC or tumor burden outside of up-to-7. Recently, two phase 3 studies showed the survival benefit of Hepatic arterial infusion chemotherapy (HAIC) for large HCC and as neoadjuvant treatment for HCC outside of Milan criteria. A Phase 3 study also showed the survival benefit of donafenib for unresectable HCC compared with sorafenib. Here, we propose a prospective randomized study to investigate the benefit of HAIC as a neoadjuvant therapy for TACE plus donafenib in unresectable BCLC B stage HCC outside of up-to seven. Methods: This is a multicenter, open-label, randomized study designed to evaluate the efficacy and safety of neoadjuvant HAIC for TACE plus donafenib compared with TACE plus donafenib in BCLC B stage unresectable HCC outside of up-to-seven. Participants are randomized in 1:1 ratio to either Arm A, receiving 2-4 cycles neoadjuvant HAIC treatment plus donafenib initially, then TACE plus donafenib sequentially, or Arm B, just receiving TACE treatment plus donafenib. HAIC consisted of infusions of oxaliplatin (35 mg/m2 for 2 hours), followed by 5-fluorouracil (600 mg/m2 for 22 hours) on day1-3 every 4 weeks. The primary endpoint is PFS, and the secondary endpoints are OS, ORR, DCR, and adverse events. We hypothesize that neoadjuvant HAIC for TACE plus donafenib will improve PFS from 6 months to 11 months, with the hazard ratio of 0.55. With one-sided significance level of 0.05 and power of 0.8, the sample size for randomization will be 156. The study, registered with clinical trial ID of NCT05171166, started enrolment in Feb 2022. As of Oct 2022, 65 patients have been enrolled and 11 patients have been randomized. Clinical trial information: NCT05171166 .
Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring ex20ins, T790M or rare mutations.
Authors: Jianchun Duan, Jun Zhao, Li Zhang, Baogang Liu, Xiubao Ren, Mingjun Li, Bo Shen, Liyun Miao, Xiumei Dai, Yueyin Pan, Yupin Li, Yu Yao, Kunyu Yang, Lin Wu, Chengzhi Zhou, Qitao Yu, Yanyan Xie, Shan Zeng, Jie Wang
Journal: Journal of Clinical Oncology (2023)

9014 Background: This study aimed to evaluate the safety and preliminary efficacy of YK-029A, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in treated or untreated patients with advanced NSCLC. Methods: This dose-escalation and dose-expansion phase 1 trial recruited previously untreated or treated patients with EGFR ex20ins mutant locally advanced or metastatic NSCLC and previously treated patients with EGFR T790M or rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. In the treatment-naïve cohort of EGFR ex20ins mutant NSCLC, patients were administered oral YK-029A 200 mg once daily in a 28-day cycle, and efficacy was assessed by the independent review committee. The study was registered (chinadrugtrials.org.cn,CTR20180350). Results: A total of 108 were included in the safety analysis set. DLT did not occur in dose-escalation phase. MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade and grade≥3 occurred in 106 (98.1%) and 41 (38.0%) patients, respectively. Treatment-related adverse events (TRAEs) of any grade and grade≥3 occurred in 102 (94.4%) and 30 (27.8%) patients, respectively. One patient had liver abscess related to YK-029A and died. Three patients terminated the treatment because of TEAEs. The most common TRAEs were diarrhea (46.3%), anemia (38.0%), and rash (32.4%). For the treatment-naïve EGFR ex20ins mutant cohort, 26 patients were included in the efficacy analysis set. Most patients were adenocarcinoma (96.4%) and at stage IV (85.7%). At the cut-off date on October 30, 2022, 19 patients (73.1%) had partial remission, five patients (19.2%) had stable disease, and two patients (7.7%) developed disease progression. The confirmed objective response rate achieved 73.1% (95% confidence interval [CI], 52.21% to 88.43%). The median progression-free survival was 9.3 months (95% CI, 5.85 to not evaluated). Conclusions: YK-029A was well tolerated and showed preliminary efficacy in treatment-naïve EGFR ex20ins mutant patients with locally advanced or metastatic NSCLC. [Table: see text]
Characterization of pre-malignant lesions in patients with pediatric neurofibromatosis type 1 using a novel whole-body magnetic resonance imaging technique.
Authors: Nicole M. Baca, Fataneh (Fae) Majlessipour, Yibin Xie, Edwin Melencio Posadas
Journal: Journal of Clinical Oncology (2023)

TPS10637 Background: Neurofibromatosis Type 1 (NF-1) patients can develop benign tumors, plexiform neuromas (PN), that may transform into malignant peripheral nerve sheath tumors (MPNST)(Tucker, et al. 2009). MPNST are rare; but in NF1, the lifetime incidence is 8-13% and MPSTs present at younger ages(Miettinen, et al. 2017). MPNST are aggressive tumors requiring full resection for best outcomes (Mautner, et al. 2008). Emerging data suggests whole-body MRI (WB-MRI) can identify NF patients with higher PN tumor burden and maybe at risk of developing MPNST. We have created a rapid, motion-robust quantitative WB-MRI technique that is likely suitable for pediatric patients. High-resolution multiparametric tissue mapping, including T1, T2, and ADC (apparent diffusion coefficient), are acquired concurrently in a single scan, as shown in prior studies (Christodoulou, et al. 2018, Ma, et al. 2020, Nguyen, et al. 2016, Wang, et al. 2020). This project will evaluate the feasibility and reproducibility of novel WB-MRI for the characterization of pre-malignant lesions in NF-1 patients. Methods: Trial Design: Pilot study of novel WB-MRI technique in pediatric NF-1 patients with a goal of 15 patients between the ages of 5-17 years. Trial MRI scans are performed at baseline, 1 month, and then 12 months (+/-3 months). A clinical 3T MR scanner (Siemens MAGNETOM Vida) performs a head-to-knee WB-MRI in 70 minutes. Signal-to-noise ratio (SNR) and imaging quality scores will be evaluated. The lesion volume and mean T1/T2/ADC are measured for each lesion on the corresponding quantitative maps based on manual ROI’s (regions of interest). To assess scan-rescan reproducibility, image quality metrics (SNR and quality score), lesion identification, and lesion characteristics (T1, T2, and ADC) will be compared between the baseline and the 1-month scan using a Bland-Altman analysis and Schuirman’s equivalence. The coefficient of variation (CV = 100 [SD/mean] %) values for each of the quantitative values will be calculated. To evaluate for lesion characterization, changes in the mean in each MRI quantitative metrics (T1, T2, and ADC) will be measured for each lesion on the baseline and 12-month visit. Spaghetti plots will be used to visualize the change over time, and the difference in mean will be tested using an appropriate parametric or nonparametric test depending on the results of tests on normality and homoscedasticity. Intervention: WB-MRI at baseline, 1 month, and 12 months (+/-3 months) Eligibility: 5 to 17 years old not requiring sedation; Clinically or molecularly diagnosed NF-1 including mosaic/segmental subjects; Not Eligible: allergy to animal dander, animal-instigated asthma, pregnant, breastfeeding, or have intrauterine device; Current Enrollment (February 2023): 5 subjects (One unable to finish a non-sedated MRI). Clinical trial information: NCT04763109 .
SGN-B6A, an integrin beta-6 (ITGB6)-targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors: Updated results from a phase 1 study (SGNB6A-001).
Authors: Antoine Hollebecque, Juanita Suzanne Lopez, Sarina A. Piha-Paul, Afshin Dowlati, Amita Patnaik, Vladimir Galvao, Bruno Bockorny, Kartik Sehgal, Ed Kingsley, Rachel E. Sanborn, Cesar Augusto Perez, Solange Peters, Mingjin Yan, Natalya N. Nazarenko, Emiliano Calvo
Journal: Journal of Clinical Oncology (2023)

3024 Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck (HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632 . [Table: see text]
Association of a high E2F targets score with survival in hepatocellular carcinoma patients.
Authors: Kohei Chida, Masanori Oshi, Arya Mariam Roy, Takafumi Yachi, Masaki Nara, Kyogo Yamada, Osamu Matsuura, Tadashi Hashizume, Itaru Endo, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2023)

4106 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Multiple staging systems have all been proposed to date; however, the optimal tool for stratification of prognosis is still not universally accepted. E2F targets are the essential component of cell proliferation, thus we hypothesized that a score to quantify E2F activity is expected to reflect the aggressiveness and prognosis of HCC. Methods: Total of 655 HCC patients from TCGA (The Cancer Genome Atlas) -HCC ( n=358), GSE6764 ( n=75), GSE76427 ( n = 115), and GSE89377 ( n=107) cohorts were analyzed. The score was generated using MSigDb Hallmark E2F Targets gene set using Gene Set Variation Analysis. Results: The E2F targets scores of TGCA-HCC patients showed a bimodal distribution, thus high vs. low score groups were divided by median. As expected, high E2F targets enriched all of the Hallmark cell proliferation-related gene sets; E2F targets, G2M checkpoint, MYC targets v1 and v2, and Mitotic spindle. It also enriched gene sets known to aggravate cancer, such as Glycolysis, mTORC1 signaling, DNA repair, and Unfolded protein response. E2F targets were significantly associated with histological grade, tumor size, and stage, as well as proliferation score and MKI67 expression. Furthermore, a higher E2F targets score was significantly associated with higher intra-tumoral genomic heterogeneity and homologous recombination deficiency, suggesting greater tumor aggressiveness. In agreement, E2F targets score correlated with the pathological progression from normal liver, cirrhosis, dysplasia, to early and advanced HCC consistently in two cohorts (GSE6764 and GSE89377). Further, the abundance of hepatocytes, fibroblasts, adipocytes, and lymphatic endothelial cells were all significantly less in high E2F HCC, which reflects proliferative cancer. On the other hand, there was no relationship between E2F and mutation rates or neoantigens. High E2F was associated with high infiltration of anti-cancerous immune cells; CD8, CD4 memory, and Th1 cells, however, there was no difference in cytolytic activity, and it did not enrich any of immune response-related gene sets. High E2F HCC was associated with worse disease-free (DFS), disease-specific (DSS), and overall survival (OS), and this was the case in both early (I and II) and late (III and IV) stages. A multivariate analysis revealed that the E2F targets score was an independent prognostic factor for OS (HR=1.68, 95%CI= 1.15–2.46, p = 0.007) as well as DSS (HR=1.81, 95%CI=1.27–2.59, p = 0.001) in patients with HCC. Conclusions: We found that the E2F targets score not only indicates cell proliferation, but also is associated with cancer aggressiveness and worse survival. Our findings suggest a possible future use of the E2F targets score as a prognostic biomarker in patients with HCC.